Project Summary Cancer and its treatment can have profound effects on skeletal muscle, the most well-recognized being atrophy, weakness and diminished oxidative capacity. These adaptations and their functional sequelae negatively impact quality of life, treatment decisions and survival. Despite these negative consequences, the factors promoting these skeletal muscle adaptations remain poorly defined and understudied in human patients. To address this gap in knowledge, our goals in this application are to: 1) to examine the role of muscle disuse as a regulator of muscle size and function in human cancer patients and 2) to understand how human tumor-derived factors and cancer therapeutics affect muscle biology and interact with muscle use/mechanical stimuli to regulate skeletal muscle size and function. Based on our preliminary data, we put forth the hypothetical model that muscle disuse accompanying cancer and its treatment plays an integral role to facilitate muscle atrophy and dysfunction in response to tumor-derived factors and chemotherapeutics in human patients and/or to mediate these adaptations directly. Accordingly, maintaining or increasing muscle use will mitigate these adaptations. Three specific aims are proposed to test this model: 1) to examine the effects of muscle disuse on skeletal muscle size, contractile function and oxidative capacity in cancer patients receiving treatment and the effects of maintaining or increasing muscle use with exercise; 2) to define the effects of human tumor-derived factors, cancer therapeutics on muscle cell size and mitochondrial function and their interaction with mechanical signaling; and 3) to determine if cancer and its treatment induce muscle contractile dysfunction through myofilament protein oxidation and whether maintaining or increasing muscle use with exercise prevents these adaptations. To accomplish these aims, we will study patients with non-small cell lung carcinoma longitudinally. Tissue acquired from skeletal muscle and tumor biopsies will be used in both in vivo and in vitro experimental approaches, along with exercise/mechanical stretch interventions. A comprehensive approach employing primary outcomes of muscle structure, function, metabolism and signaling, ranging from molecular to whole tissue measurements, will provide data to address these aims. Achieving our goals will advance knowledge of the cellular and sub-cellular skeletal muscle adaptations in human cancer patients undergoing treatment and the mediators of these adaptations. If successful, our results could shift conventional thinking in this field to include disuse as an important effector of muscle adaptations in human cancer. Such findings could influence supportive care paradigms, which currently focus on rehabilitating cancer patients after therapy, to support institution of activity/exercise interventions earlier in the clinical treatment continuum to more effectively mitigate muscle adaptations and, in turn, improve the quality and duration of life.